Nonhomologous end joining (NHEJ) is a major pathway for resolving chromosome double strand breaks. We have determined NHEJ's pivotal role in maintaining genome stability is at least in part due to a unique ability to cope with the complex broken end structures expected. We will address here if this is because NHEJ is adaptive - if it can sense differences in the type of damage, and tailor its path to resolution accordingly. In Aim 1 we will address possible mechanisms for its unique ability to bypass the more subtle classes of damage at ends. In Aim 2 we will address the role of three enzymes that are highly specific for removing different types of damage from ends. We will determine how end cleaning enzymes help define a next line of defense, to aid in resolving damaged ends when the damage cannot be bypassed. In Aim 3 we will investigate the role of Artemis, a nuclease, which also removes damage from ends but which does not appear to be specific for a given type of damage. We will determine if Artemis defines the last line of defense, and helps remove damage at ends that could neither be bypassed nor cleaned. The effectiveness of some cancer therapies - radiation and certain chemotherapy agents - relies to a great degree on their ability to generate complex end structures that interfere with repair by NHEJ. Our studies will clarify the mechanism of resolving these ends, and how the mechanism can be manipulated to make therapies more effective and safer.